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Objectives To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille CalmetteGuérin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity. Patients and methods Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weeklyrsix and thereafter fortnightlyrsix) either with the standard or RD instillation. Results All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (SD) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose. Conclusion Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with highrisk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediaterisk lesions and for maintenance schedules.

Summary The role of two common polymorphisms of enzymes involved in the metabolism of drugs and carcinogens was studied in relation to prostate cancer. The gene encoding one of these enzymes (NAT2) is located in an area where frequent allelic loss occurs in prostate cancer. Mutations at the genes CYP2D6 and NAT2 were analysed by allele-specific polymerase chain reaction and restriction mapping in DNA from 94 subjects with prostate cancer and 160 male healthy control subjects. Eleven prostate specimens were analysed for genotype and enzymatic activities NAT2, CYP2D6 and CYP3A by using the enzyme-specific substrates sulphamethazine and dextromethorphan. Enzyme activities with substrate specificities corresponding to NAT2, CYP2D6 and CYP3A are present in human prostate tissue, with mean ± s.d. activities of 4.8 ± 4.4 pmol min-' mg-' protein, 156 ± 91 and 112 ± 72 nmol min-' mg-' protein respectively. The Km, values for the prostate CYP2D6 and CYP3A enzyme activities corresponded to that of liver CYP2D6 and CYP3A activities, and the CYP2D6 enzyme activity is related to the CYP2D6 genotype. The N-acetyftransferase, in contrast, had a higher Km than NAT2 and was independent of the NAT2 genotype. The CYP2D6 and CYP3A enzymes, and an N-acetyttransferase activity that is independent of the regulation of the NAT2 gene. are expressed in human prostate tissue. The presence of carcinogen-metabolizing enzymes in human prostate with a high interindividual variability may be involved in the regulation of local levels of carcinogens and mutagens and may underie interindividual differences in cancer susceptibility. 1362 JAG Agundez et al due to a strong local effect on the actixation or deactivation of carcinogens in situ. For instance. it has been shovA-n that N-acetvltransferase polx morphism play s a relevant role in the formation of 2-aminofluorene-DNA adducts in tumour target organs (Feng et al. 1996). In an attempt to elucidate the events that occur as previous steps to prostate carcinogenesis. x e hax e studied A hether the poix-morphic enzymes CYP2D6 and NAT2 are actix ely expressed in human prostate tissue. as well as the impact of such genetic polx morphisms in prostate cancer susceptibility. In order to ex aluate w-hether allelic loss of these genes occurs in adenomatous prostate tissue. the occurrence of allelic losses at the CYP2D and .VA72 gene loci in prostate tissues was also studied. If the CYP2D6 enzyrme is functionally expressed in prostate. allelic loss of CYP2D6 could cause changes in local enzyme activity. modifving the local metabolism of carcinooens and mutarens. To our know-ledge. no studies involving allelic loss of the polymorphic gene CYP2D6 haxe been performed. This is also the first study inxolxing allelic loss of the NVA72 gene in prostate. Indeed only one study involvin2 allelic loss of NAT2 has been published. and it was performed in colon cancer (Hubbard et al. 1997). Keywords METHODS Patients and controlsAll the subjects included in this studx were unrelated v hite Spanish men. samples from t...

1. Alteration in the flow of blood to the penis is thought to be the most frequent organic cause of erectile dysfunction or impotence. However, information concerning the penile small arteries (helicine arteries) which control blood flow between the arterial systemic circulation and the cavernous sinusoids is scarce. Therefore, the purpose of the present study was to investigate the involvement of nitric oxide, which is considered to be the main neurotransmitter in corpus cavernosum, in both the non-adrenergic non-cholinergic inhibitory neurotransmission and the endothelium-dependent responses in human penile small arteries. 2. Penile small arteries (lumen diameter 200-700 microns), which were branches of the human deep penile arteries obtained either from patients undergoing penile surgery or from organ donors, were mounted in microvascular myographs for isometric tension recording and electrical field stimulation was performed in the presence of guanethidine and atropine to block adrenergic neurotransmission and muscarinic receptors, respectively. 3. In phenylephrine-contracted penile small arteries, electrical field stimulation (0.5-32 Hz) induced frequency-dependent relaxations of both endothelium-intact and -denuded preparations. The inhibitor of nitric oxide synthase, NG-nitro-L-arginine (3 x 10(-5) mol/l), abolished the relaxations at the lowest frequencies, while slow-developing relaxations were still observed at high frequencies (16 and 32 Hz). The inhibitory effect of NG-nitro-L-arginine was reversed in the presence of L-arginine (3 x 10(-3) mol/l). Tetrodotoxin totally abolished the relaxations to electrical field stimulation. In contracted small penile arteries in the presence of NG-nitro-L-arginine, the nitrovasodilator sodium nitroprusside induced potent relaxations. 4. The endothelium-dependnet vasodilator acetylcholine induced relaxations of penile small arteries, which were only partially reduced in the presence of NG-nitro-L-arginine. In contrast, the relaxations to acetylcholine of trabecular corpus cavernosum preparations were almost abolished in the presence of NG-nitro-L-arginine. 5. The present study suggests that relaxations of human intracavernosal small penile arteries induced by non-adrenergic non-cholinergic nerve stimulation partially involve nitric oxide and also another inhibitory transmitter causing relaxations resistant to nitric oxide synthase blockade. In addition, endothelium-dependnet relaxations in human small penile arteries are mediated by both nitric oxide and a factor resistant to NG-nitro-L-arginine.

The purpose of this work is to evaluate radiation doses to the lens of urologists during interventional procedures and to compare them with values measured during interventional radiology, cardiology and vascular surgery. The measurements were carried out in a surgical theatre using a mobile C-arm system and electronic occupational dosimeters (worn over the lead apron). Patient and staff dose measurements were collected in a sample of 34 urology interventions (nephrolithotomies). The same dosimetry system was used in other medical specialties for comparison purposes. Median and 3rd quartile values for urology procedures were: patient doses 30 and 40 Gy cm(2); personal dose equivalent Hp(10) over the apron (μSv/procedure): 393 and 848 (for urologists); 21 and 39 (for nurses). Median values of over apron dose per procedure for urologists resulted 18.7 times higher than those measured for radiologists and cardiologists working with proper protection (using ceiling suspended screens) in catheterisation laboratories, and 4.2 times higher than the values measured for vascular surgeons at the same hospital. Comparison with passive dosimeters worn near the eyes suggests that dosimeters worn over the apron could be a reasonable conservative estimate for ocular doses for interventional urology. Authors recommend that at least the main surgeon uses protective eyewear during interventional urology procedures.